01 mass spectrometry 101 final hofstadler

8/6/2019 01 Mass Spectrometry 101 FINAL Hofstadler

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Technology Transition Workshop

Disclaimer

This presentation covers the basic concepts ofmass spectrometry

The material is not specifically required to operate

the Ibis T5000

Users are not expected to tune and/or optimize themass spectrometer

The goal of this presentation is to give the user abasic understanding of where/how massspectrometry fits into the Ibis workflow


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Overview

Introduction what is Mass Spectrometry? Mass Spectrometry (MS) and Ibis T5000

Brief History

General Components

The Mass Spectrum Definitions and Nomenclature

Ionization Sources

Matrix Assisted Laser Desorption Ionization (MALDI)

Electrospray Ionization (ESI) Others

Time-of-Flight (TOF) Mass Analyzers

ESI-TOF of nucleic acids


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Mass Spectrometry and Ibis platform

Profile 1

Profile 2

Profile 3

Forensic profile compared with existing databaseentries, or used to populate database

IMAGE COURTESY OF IBIS BIOSCIENCES, INC.


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Mass Spectrometry of Nucleic Acids?

Information content From precise mass measurements unambiguous basecompositions are derived [A10 G23 C32 T17] = [10 23 32 17]

Speed < 1 minute/sample

Applicability to mixtures Dynamic range is around 100:1 MS succeeds where sequencing fails (e.g. mixtures)

Automation End-to-end process is highly automated (including spectral

processing/interpretation)

Sensitivity Single copy detection demonstrated with PCR front-end


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What is a Mass Spectrometer?

An instrument which measures the mass-to-charge ratio(m/z) of ionized analyte based on its response to appliedelectric and/or magnetic fields

atoms, molecules, clusters, and macromolecularcomplexes

The m/zmeasurement is converted to a mass measurement mis in atomic mass units or Daltons (Da)

1 Da = 1/12 the mass of a single atom of 12C

1 Da = 1.66 x 10-24 grams

zis an integer multiplier of the fundamental unit of charge

(q) q = 1.602 x 10-19 Coulombs

Mass = m/z X z

A mass spectrometer is essentially a molecular (or atomic)scale that weighs analytes of interest


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Brief History 1897 J.J. Thompson announced the presence of electrons or

corpuscles based on the deflection of cathode rays byelectric and magnetic fields

He later used this beam-deflection device to measure themass of the electron (1906 Nobel Prize)

+ -

IMAGE COURTESY OF:https://reader009.{domain}/reader009/html5/0515/5afa1fff697fd/5afa2004707f9.jpg

IMAGES COURTESY OF STEVEN A. HOFSTADLER, PH.D.
http://www.manep.ch/img/photo/challenges/nanotubes/thompson.jpghttp://www.manep.ch/img/photo/challenges/nanotubes/thompson.jpg


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Brief History (cont.) 1919 F. W. Aston used Thompsons mass spectrometer to

measure the atomic masses of 30 gaseous elements andprove the existence of multiple isotopes. Relative abundancemeasurements were made by recording isotope lines on film.Mass spectroscopy Nature1919; 104; 393. (1922 NobelPrize)

Design principles are the basis of modern electric and magneticsector instruments

Astons original Positive-Ray Mass Spectrograph

IMAGE COURTESY OF SCIENCE MUSEUM/SCIENCE & SOCIETY PICTURE LIBRARY:http://www.ingenious.org.uk/site.asp?s=S2&DCID=1927-1085
http://www.ingenious.org.uk/site.asp?s=S2&DCID=1927-1085http://www.ingenious.org.uk/site.asp?s=S2&DCID=1927-1085


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Basic Components

Inlet System

sample introduction

Ion Sourceionizes sample

Ion Analyzersort ions by m/z

Ion Detectorcounts ions

Data Systemsignal processor

Mass Spectrum

Vacuum chamber

Instrument Control Computercontrols timing and voltages

ionoptics

ionoptics

IMAGE COURTESY OF STEVEN A. HOFSTADLER, PH.D.


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The Mass Spectrum

300 400 500 600m/z

RelativeAbun

dance

ArbitraryIntensity

DetectorResp

onse

100

50

0

25

75



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The Mass Spectrum

/disk2/data/12_4/628_23426/11/pdata/1xspec MonDec 7 19:16:471998

200 300 400 500 600m/z

397.13 397.18

C15H16F6N4O2397.1104

C19H22N6O4397.1628

(M-H)-

M/M > 75,000



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The Isotopic Envelope

Most elements have more than 1 isotope

For a given atom type, different isotopes havedifferent numbers of neutrons e.g. an atom of 12C has 6 neutrons, 6 protons, and 6

electrons an atom of 13C has 7 neutrons, 6 protons, and 6

electrons

The mass of a neutron is 1.00867 Da

Each element has different numbers and relativeabundances of other isotopes: 12C = 98.90% 13C = 1.10% 35Cl = 75.77% 37Cl = 24.23% 19F = 100%


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The Isotopic Envelope

Unless a molecule is composed of onlymonoisotopic elements, there is a finite probabilitythat it will contain one or more heavy isotopes

The relative abundance of the monoisotopic peak

decreases with increasing mass Observed distribution is the sum of isotopic

contributions from all hetero-isotopes

Except in a few cases, isotopic fine structurecannot be resolved e.g. for an N+2 peak the contributions from 2 13C and 1 18O

cannot be resolved

Consider carbon clusters:


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Isotope Distributions of Carbon

8.0106 12.010 16.009 20.009

C1

MW

1193.1 1197.1 1201.1 1205.1 1209.1

C100

MW

11979 11995 12011 12027 12043

C1000

MW

12C = 100%

13C = 1.1%

12C = 89.1%

13C = 100%

213C = 54.6%

12C = 0.01%

1113C = 100%

2013C = 3.9%



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Definitions and Nomenclature Resolution : M/M

actually (m/z)/(m/z) (m/z) : peak width at full width half maximum (FWHM)

0

33

66

100

1201.8 1203.8 1205.8 1207.8 1209.8

m/z

r

t

m/z = 1.20

RelativeAbundanc

e

Resolution (FWHM) = 1205.8

1.20= 1005



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Definitions and Nomenclature

Resolution (cont.) can be limited by the inherent width of the isotope envelope

step function to isotopic resolution

need M/M > molecular weight for isotopic resolution

0

33

66

100

1201.8 1203.8 1205.8 1207.8 1209.8m/z

r

t

m/z = 0.12

RelativeAbundance

Resolution (FWHM) = 1205.240.12

= 10044



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Definitions and Nomenclature:Mass Measurements3 ways to specify molecular weight

Monoisotopic Molecular Weight

All 12C, 14N, 16O, etc.

most accurate method for low

MW species

monoisotopic peak is base peak(i.e. most abundant peak) up to

about 2 kDa

Average Molecular Weight

most commonly used

few MS platforms can resolve

isotopes for analytes > 5 kDa between monoisotopic and

average increases with increasing MW

MWmi

MWave



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Definitions and Nomenclature:Mass Measurements (cont.)3 ways to specify molecular weight

Most Abundant Isotope Molecular Weight

not widely used

convenient for high MW, isotopically resolvedspecies

24622 24638 24654 24670 24686

C780 H981 N300 O478 P79

mass

MWmost abundant isotope



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Definitions and Nomenclature

Mass Measurement Accuracy|(m/z)theory - (m/z)measured|

(m/z)theory= Mass Measurement Error (ppm)

cmpd Mcalc Mmeas m ppmC15H16F6N4O2 397.1105 397.1104 0.0001 0.25C19H22N6O4 397.1630 397.1628 0.0002 0.50

397.13 397.18

C15

H16

F6N

4O

2397.1104

C19H22N6O4397.1628

(M-H)-

M/M > 75,000



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Mass Spectrometry Nuts and Bolts

Ionization Sources

Mass Analyzers


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Ionization Sources

Ionization is the process by which analytes arecharged

Adding or removing electrons (e-) (MW = 0.0006 Da)

Adding or removing protons (H+) (MW = 1.0078 Da)

Several very effective methods for ionizing lowmolecular weight and/or volatile compounds.Limited MS to analytes with molecular weightsunder ~1 kDa

In the 1980s, two ionization methods developedfor ionizing high molecular weight analytes

MALDI & ESI


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Ionization Sources for Low MW Analytes

APCI Atmospheric Pressure Chemical Ionization formation of analyte ions through charge exchange with

ionized carrier gas

EI Electron Ionization generation of ions by bombarding gas phase molecules

with high energy electrons analyte must be volatile

ionization energy dictates

extent of fragmentation

still widely used w/ GC



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laser

Ionization Sources - MALDI Matrix Assisted Laser Desorption Ionization

Sample is co-crystallized with a matrix which absorbsphotons and creates a desorption plume that ionizes thesample

Gentle ionization technique (harsher than ESI)

A pulsed ion source Produces singly charge ions

Relatively salt tolerant

Effective for wide range of MWs

Fast and automatable



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Ionization Sources - ESI Electrospray Ionization

Ions are desolvated/desorbed from highly charged liquid droplets

Generates multiple charge states of large analytes

results in folded-over spectra which can be recorded over narrower m/zrange

Very soft ionization technique

applicable to labile molecules and noncovalent complexes

Low tolerance for nonvolatile salts, buffer additives, and detergents

rigorous sample clean-up required for some applications

High sensitivity

applicable to analyte concentrations < 100 nM



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A Negative Ionization Mode ESI Mass Spectrumof a Low MW Analyte: Singly Charged Spectrum

Well A03

Q:\roboticsdata\archive\completed\P00005666\3\acqus

477.07 587.09 708.52 841.36 985.6 1141.25 1308.3 1486.76 1676.63 1877.9 2090.58

m/z

0.00

4648

9296

13944

18592

m/z= 1347.10

MW = 1347.10 + MWproton= 1348.11 Da


(M-H+)1-


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An ESI (+) Mass Spectrum of a High MW Analyte(Carbonic Anhydrase Protein MW = 28,821 Da)

What dont we know:Molecular Weight?

Which Charge States?What are all these peaks?

What do we know:m/zof lots of peaksAdjacent peaks differ by 1 charge

700 800 900 1000m/z

1100

RelativeInt

ensity



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Conventional Deconvolution of ESI-MS Spectrum

700 800 900 1000m/z 1100

RelativeIn

tensity

From m/z of peaks and z, calculate z of one peak.

961.7 = m/z1

994.8 = m/z2

m/z1 m/z2

m/z2= z1

33.1

994.8= z1= 30



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700 800 900 1000m/z

1100

RelativeIn

tensity

961.7 (M+30H+)30+

MW = (961.7 x 30) (30 x 1.0078)= 28,821 Da

accuracy improved by averagingacross multiple (all) charge states

Conventional Deconvolution of ESI-MS SpectrumUse zand m/zto calculate mass



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ESI-MS of DNA

Phosphodiester backbone iseasily deprotonated at high pH

ESI most effective in negativemode (in positive ionizationmode basic groups on bases areprotonated)

Both backbone and nucleobaselinkages to sugar are relativelylabile

We have optimized solution andinterface conditions for DNAanalysis by mass spectrometryover the past 10 years

HO

N

NN

N

NH2

O

HO

HH

HH

PO

O

O-

N

NH2

ON

O

HO

HH

HH

PO

O

O-

NH

N

N

O

NH2N

O

H

HH

HHO

PO

O-

O-



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Then and NowThen (1981)

Pre-contributions of Fenn,Tanaka, Hillenkamp/Karas

20-mer DNA

Cf252 desorption - TOF

M/M ~ 25 MW = 6301 + 5 (~ 800 ppm)

Now

Additional contributionsfrom Marshall,McLafferty, McLuckey,Smith and others

120-mer DNA acquired infully automated modality

ESI-FTICR

M/

M = 150,000 MW = 37,091.18 + 0.04

~ 1 ppm

1001.0 1002.0 1003.0 1004.0

(M-37H+)37-

900 1000 1100m/z

1200

*

43-

41-

39- 37-

35-

33-

31-



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An ESI Mass Spectrum of a PCR Productdoublet peaks at each charge state correspond to

forward and reverse strands of amplicon

800 900 1000 1100 1200 1300m/z

33-31-

29-

27-

25-

35-

37-

39-

41-

800 900 1000 1100 1200 1300m/z

33-31-

29-

27-

25-

35-

37-

39-

41-



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Raw ESI-MS spectrum from 3-plex PCR mix

Internalmass

calibrant

Internalmass

calibrant

Internal mass calibrants bracketthe spectrum for accurate

calibration of the measurementsbefore deconvolution



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Deconvolved ESI-MS spectrum from 3-plex PCR

30,000 32,000 34,000 36,000 38,000 40,000 42,000 44,000

0

1000

2000

3000

4000

5000

6000

Mass (Da)

Signalintensity

3285

5.1

34143.8

37058

.2

37254.2

42162.1

42710

.3



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Masses to Base Composition

Requires 25 ppmmass measurement error

Math takes into accountWatson-Crick base pairing


Microsoft Media Elements




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Masses to Base Composition

Require masses of both strands and fact that thestrands are complimentary to determine basecomposition

Single Strand: 32889.450 Da

(+ 25 ppm or 0.75 Da): 928 base comps(+ 1 ppm or 0.03 Da): 82 base comps

Single Strand: 33071.462 Da(+ 25 ppm or 0.75 Da): 948 base comps

(+ 1 ppm or 0.03 Da): 95 base comps

ppm: part per millionDa: Dalton (atomic mass unit)


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Exact Mass Measurements of Both Strands FacilitatesUnambiguous Base Composition Determination

ppm0-2550

100250500

# comp pairs1

13

663781447

AwGxCyTz

AzGyCxTwIMAGE COURTESY OF IBIS BIOSCIENCES, INC.


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Mass Measurement and the Canadian Nickel

Penny = 2.500 g

Nickel* = 3.950 gDime = 2.268 g

Quarter = 5.670 g

A = 313.0576 amuG = 329.0526 amu

C = 289.0464 amu

T = 304.0461 amu

The Coins and Scale analogy doesnt work if

using all US coins as a US Nickel weighs 5.000 g Thus 5 g could be two pennies or one nickel

Interesting parallel to nucleobases with massmeasurement error

A mass shift of 15 + 1 Da could be a A -> G ora C -> T

A double SNP A -> G and T-> C would result ina 1 Dalton difference

A one Dalton uncertainty is consistent withtwo base compositions




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Mass Measurement and the Canadian Nickel

Penny = 2.500 g

Nickel* = 3.950 gDime = 2.268 g

Quarter = 5.670 g

A = 313.0576 amuG = 329.0526 amu

C = 289.0464 amu

T = 304.0461 amu

The Coins and Scale analogy doesnt work ifusing all US coins as a US Nickel weighs 5.000 g

Thus 5 g could be two pennies or one nickel

Interesting parallel to nucleobases with massmeasurement error

A mass shift of 15 + 1 Da could be a A -> G ora C -> T

A double SNP A -> G and T-> C would result ina 1 Dalton difference

A one Dalton uncertainty is consistent withtwo base compositions

We have a Canadian Nickel nucleobase

13C labeled guanosine shifts the mass by 10Da per incorporation

No confusion over which SNP is present

No uncertainty as to whether the A/G T/Cdouble SNP is present

G = 339.1662




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881.5 883.14 884.79 886.43 888.08 889.73 891.38 893.03 894.69 896.34 898m/z

A48 G18 C31 T40

A47 G19 C32 T39

42030.19 Da42478.39 Da

42031.18 Da42479.38 Da

Without mass tag:Product strands differ by 1 Da for two products that differ by a GA and CT SNP atthe same time.

Some double SNPs cause small mass differences

High mass precision and mass tag combine to provideunambiguous base compositions in routine operation




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With mass tag:

With 13C-dGTP, the mass separation increases to ~10 Da for each strand

Correspondinguntagged peaks

=

881.5 883.14 884.79 886.43 888.08 889.73 891.38 893.03 894.69 896.34 898m/z

A48 G18 C31 T40

A47 G19 C32 T39

42187.02 Da

42694.04 Da

42197.81 Da42704.83 Da

Mass tag increases mass separation for theseSNPs




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30,000 32,000 34,000 36,000 38,000 40,000 42,000 44,0000

1000

2000

3000

4000

5000

6000

Mass (Da)

Signalinten

sity

32855.1

34143.8

[A40 G9 C40 T19]

37058.2

37254.2

[A47 G18 C25 T30]

42162.1

42710.3

[A49 G17 C31 T40]



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Size Constraints

We generally characterize PCR products < 150 bp(~47 kDa/strand)

In general, 25 ppm mass measurement error or

better will provide unambiguous base compositionfor double stranded products < 150 bp

Analysis of larger products is feasible, but

information content is lower Spectra more congested

Math not in our favor


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Technology Transition Workshop299 bp PCR product on ESI-TOF (well 9/24)

700 900 1100 1300 1500 1700 1900 m/z

2000

4000

6000

8000

10000

12000

a.i.

91000 92000 93000 94000 mass

Meas. MWave = 91009.4

Theo. MWave = 91008.7ppm error = 7.7

Meas. MWave = 93601.9

Theo. MWave = 93601.0

ppm error = 9.6

(M-100H+)100-



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Number of possible base compositions asa function of ppm mass error and mass

ppmError

SS1 SS2DS

MWave=91008.7 MWave=93601.0

1 2563 2580 1

5 12846 14296 3

10 25809 29054 10

20 * x x 62

25 x x 89

50 x x 367

*Average ESI-TOF error over 24 replicates of 299-mer


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ESI Parameters Ion desolvation is controlled by several parameters

Temperature of desolvation gas

Capillary-skimmer potential difference

Pressure in capillary-skimmer interface region

Excessive activation in the interface region can lead to dissociation

DNA is labile relative to proteins and one must use gentleinterface conditions

skimmercone

rf-only hexapole

gateelectrode

inletcapillary

turboPump

ESIplume

roughpump

turbodragpump

coldcathodegauge

heatedcounter-current

gasflow

To MS



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Solution/Desolvation Conditions(same sample analyzed under different source conditions)

ESI-TOFPCR product from E. Colidetected as single strands

ESI-TOFPCR product from E. Colidetected as intact duplex



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Effect of Capillary-Skimmer Potential Difference20-mer phosphorothioate oligonucleotide

(M-6H+)6-

(M-4H+)4-(M-8H+)8-

(M-6H+)6-

(M-4H+)4-(M-8H+)8-

500 700 900 1100 1300 1500m/z

1700500 700 900 1100 1300 1500m/z

1700

w3(1-)

a4-base(1-)

a4(1-)

w3-A-H2O(1-)

a3-base(1-)

Vcap = -54 V

Vcap = -128 V



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Salt is a Killer

Nonvolatile counterions (e.g. Na+

, K+

, Mg2+

, etc) arenot removed during desolvation High concentrations can preclude the generation of a

stable ESI plume

Oligonucleotides are more vulnerable tocontamination than proteins Phosphodiester backbone is highly anionic

Larger oligonucleotides more salt intolerant than smallerones

Effects of salt can be partially mitigated by choiceof buffers See Griffey et al. RCMS 1995; 9; 97-102.


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Salt is a KillerESI-MS of 20-mer phosphorothioate oligonucleotide

500 700 900 1100 1300 m/z0

1 x 106

500 700 900 1100 1300 m/z0

2.1 x 107

Intensity

Intensity

1 mM Na+

10 M Na+

1050 10901050 1090

1050 10901050 1090

MW?

MW



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Technology Transition WorkshopComparison of raw data for adducted vs.

non-adducted mass spectrum

Well F01Q:\roboticsdata\archive\completed\P00005563\61\acqus

865 870.52 876.06 881.62 887.19 892.78 898.39 904.02 909.66 915.32 921

m/z0.00

16545.5

33091

49636.5

66182

Well F12Q:\roboticsdata\archive\completed\P00005563\72\acqus

865 870.52 876.06 881.62 887.19 892.78 898.39 904.02 909.66 915.32 921

m/z

9635.5

19271

28906.5

38542

48177.5

57813

67448.5

77084

Adducted

Not adducted



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Mass Analyzers

All work by measuring the response of chargedparticles to electric and/or magnetic fields

All work at reduced pressure to reduce ion-neutralcollisions

Want to minimize scatter and/or neutralization

Typical operating pressures

Linear quadrupoles ~ 5 x 10-5 torr

FTICR < 10-9 torr TOF 10-5 10-7 torr


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Highlights of TOF-MS Advantages:

Simple and rugged benchtop construction

Theoretically unlimited mass range

Adaptable to many ionization sources

Fast acquisition - signal averaging to improve S/N

Mass accuracy rivals that of FTICR Disadvantages:

Limited resolution

Theoretically limited to detection electronics

Practically limited by energy and spatial spreads in ions

TOF is inherently pulsed Must wait for longest flight time ions before sending next packet of

ions (Hz to kHz typical repetition rates)

Cannot simultaneously measure all m/zvalues

This is mitigated by external ion accumulation


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Time-of-flight (TOF) Mass Analyzers

Ions are accelerated by electric field (V/d)

Ions then drift at their final velocity for a fixed distance

Ions impact a detector and their flight time is recorded

flight time is

proportional to velocity

proportional to the square root of m/z

dVvz

mmvEK /

2

1

2

1..

22 =

=

t = L/ = L m/2zVt: sec L: meters : velocity m: kg z: Coulombs V: voltslower m/zions reach higher velocity than higher m/zions

where is velocity, V/d is field strength


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TOF-MS Detection Schemes Particle impact, electron generation, and detection

Electron Multiplier

Microchannel Plate

Hybrids or Other particle detectors

Simplest example: metal foil

Most common: microchannel plate

Array of tilted glass channels 2-10 microns

Electron cascade=gain

Also used in night vision

ion Electrons (a few)

ion 106

- 1012

electrons



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Mass Analyzers - TOF

Linear Geometry Ions drift in field-free region, but energy spread (+E)

leads to time spread (-T) (more energy gives shorterTOF)


T h l T i i W k h


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Mass Analyzers - TOF Reflectron

Ions drift, but at ion mirror they turn around

+E (energy spread) leads to deeper penetration in ionmirror

Linear config: +E leads to -T Reflectron config: +E leads to -T+T (=0; energy spread

eliminated at detector)

Diagram for single m/zion withenergy difference

E+E


T h l T i i W k h


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ESI with an External Ion Reservoir ESI is a continuous ionization source while most MS

platforms are most effectively coupled to pulsed sources Couple external ion reservoir with ESI to make a pulsed

ionization source

Nearly 100% ionization duty cycle

Ions are externally accumulated while others are being mass

analyzed

skimmercone

rf-only hexapole

gateelectrode

inletcapillary

turboPump

ESIplume

roughpump

turbodragpump

coldcathodegauge

heatedcounter-currentgas flow

To MS

skimmercone

rf-only hexapole

gateelectrode

inletcapillary

turboPump

ESIplume

roughpumproughpump

turbodragpump

coldcathodegauge

heatedcounter-currentgas flow

To MS


T h l T iti W k h


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Mass Spectrometry and T5000

Profile 1

Profile 2

Profile 3

Forensic profile compared with existing databaseentries, or used to populate database


T h l T iti W k h


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Conclusions In general, mass spectrometry is used to weigh molecular

analytes of interest

Electrospray ionization is employed as it can promote large,intact oligonucleotides into the gas phase

Time-of-Flight mass spectrometry is used as it providesaccurate molecular weight measurements in a robust,benchtop, instrument format

As part of the Ibis process, amplified DNA is weighed with

enough accuracy to unambiguously determine basecomposition [AGCT]

Base composition profiles can be compared to other profilesand/or databases

T h l T iti W k h


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Abbreviations and Jargon

APCI atmospheric pressure chemical ionization

bp base pair(s)

CAD collisionally activated dissociation

Da Dalton = atomic mass unit

DNA deoxyribonucleic acid

Ds double stranded (DNA)

EI electron impact (ionization)

ESI electrospray ionization

FAB fast atom bombardment

FD field desorption (ionization)

FI field ionization

FTICR Fourier transform ion cyclotron resonance

FTMS Fourier transform mass spectrometry

FWHM full width half maximum (used to specify resolution)

GC gas chromatography

Hz Hertz (cycles/second)

IRMPD infrared multiphoton dissociation

kDa kilo Dalton(s)

m/m mass divided by peak width (mass resolution)m/z mass to charge ratio

MALDI matrix assisted laser desorption ionization

MSAD multipole storage assisted dissociation

mtDNA mitochondrial deoxyribonucleic acid

MW molecular weight

PCR polymerase chain reaction

PD plasma desorption

ppm parts per million

QIT quadrupole ion trap

Q-TOF quadrupole-time-of-flight

rf radio frequency

SIMS secondary ion mass spectrometry

ss single stranded (DNA)

TOF time-of-flight

TSP thermospray (ionization)

T h l T iti W k h


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Contact Information:

Steven A. Hofstadler, Ph.D.

Ibis Biosciences, Inc.

Email: [email protected]
mailto:[email protected]:[email protected]

01 mass spectrometry 101 final hofstadler

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